Cell and Gene Replacement Strategies for Arginase Deficiency
精氨酸酶缺乏症的细胞和基因替代策略
基本信息
- 批准号:9289701
- 负责人:
- 金额:$ 34.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:ARG2 geneAddressAdolescentAffectAgeAmmoniaAnimalsArginineBehaviorBehavioralBiochemicalBirthCell TherapyCellsClinicalCongenital neurologic anomaliesCytokinesisDNA Sequence AlterationDataDevelopmentDifferentiated GeneDiseaseDrug Metabolic DetoxicationEncapsulatedEngraftmentEnzymesExtrahepaticGene ExpressionGene Transduction AgentGenesGenomicsGoalsGrantGrowthGrowth FactorHepaticHepatocyteHumanHydrogelsHyperammonemiaHyperargininemiaImmune responseImpairmentInfiltrationInjectableInvestigationKidneyKnockout MiceLeadLearningLifeLiverLongevityMammalsMediatingMetabolismMethodsMusMuscleMuscle CellsNanotechnologyNeonatalNervous System TraumaNeuronsNewborn InfantNitrogenOne-Step dentin bonding systemPathway interactionsPatientsPeriodicityPeripheralPhenotypePlasmaPrimary carcinoma of the liver cellsProductionProstateProtein IsoformsPsyche structureRecombinantsResearchRiskSiteSpasticStem cell transplantStem cellsTechnologyTestingTimeTissue EngineeringTissuesUreaViral Vectoradeno-associated viral vectorarginasebasebehavior testclinical applicationeffective therapyenzyme deficiencyexperimental studygene correctiongene replacementgene therapygenome editingimprovedinduced pluripotent stem cellknockout animalliver cell proliferationmouse modelmuscle formnanoencapsulatednovel strategiesnovel therapeuticsnull mutationpromoterscaffoldspasticityurea cycle
项目摘要
Project Summary/Abstract
The urea cycle is the major pathway for detoxification of ammonia in mammals. Arginase 1 deficiency is thought
to be the least common of the urea cycle disorders and results in hyperargininemia. In humans, deficiency of
this enzyme is characterized clinically by progressive mental impairment, spasticity, growth retardation, and
periodic episodes of hyperammonemia. This proposal is two-fold: 1) to continue to advance gene-based
therapies for arginase deficiency utilizing appropriate murine models; viral vectors and genomic correction
technology will be applied to examine if animals can be corrected behaviorally and biochemically; and 2) to
evaluate an iPSC-derived cell therapy approach with hepatocytes placed on bioactive scaffolds to supply urea
cycle function. Preliminary data: Our research group has (amongst other findings): 1) constructed and
characterized the arginase 1 knockout mouse; 2) demonstrated long-term survival and rescue with recombinant
adeno-associated viral vectors; 3) demonstrated that only low-level ureagenesis is necessary for long-term
survival; 4) shown that, using an array of behavioral tests, that treated arginase knockout animals lack nervous
system abnormalities and there is no difference in learning or behavior when compared to littermates; 5) shown
that peripheral metabolism can result in control of circulating plasma arginine; and 6) loss of arginase gene
expression results in abnormalities of intrinsic excitability and the dendritic arbor of neurons. In Aim 1, long-term
expression of arginase 2 in muscle by viral vector gene therapy will be performed to examine for biochemical and
phenotypic correction in a murine model of arginase deficiency. This approach may avoid neutralizing immune
responses in patients with null mutations. In Aim 2, studies will examine if an auxiliary liver grown on scaffolds
can supply the minimal urea cycle function necessary to lead to phenotypic correction of hyperargininemia. This
approach may be successful for other urea cycle disorders. With successful completion of the proposed studies it
is expected that a new therapy with gene and cell replacement will be one step closer for patients afflicted with
arginase deficiency.
项目概要/摘要
尿素循环是哺乳动物氨解毒的主要途径。精氨酸酶 1 缺乏症被认为
是最不常见的尿素循环障碍,并导致高精氨酸血症。在人类中,缺乏
这种酶的临床特征是进行性精神障碍、痉挛、生长迟缓和
周期性发作的高氨血症。该建议有两个方面:1)继续推进基于基因的研究
利用适当的小鼠模型治疗精氨酸酶缺乏症;病毒载体和基因组校正
将应用技术来检查动物是否可以在行为和生化方面得到纠正; 2) 至
评估 iPSC 衍生细胞治疗方法,将肝细胞放置在生物活性支架上以供应尿素
循环功能。初步数据:我们的研究小组(除其他发现外):1)构建并
精氨酸酶 1 敲除小鼠的特征; 2)通过重组证明了长期存活和救援
腺相关病毒载体; 3)证明只有低水平的尿素生成对于长期而言是必要的
生存; 4)表明,通过一系列行为测试,经过治疗的精氨酸酶敲除动物缺乏紧张感
系统异常,与同窝出生的孩子相比,学习或行为没有差异; 5) 如图所示
外周代谢可导致循环血浆精氨酸的控制; 6) 精氨酸酶基因丢失
表达导致神经元内在兴奋性和树突状结构的异常。在目标 1 中,长期
将通过病毒载体基因治疗在肌肉中表达精氨酸酶 2,以检查生化和
精氨酸酶缺乏的小鼠模型的表型校正。这种方法可以避免中和免疫
无效突变患者的反应。在目标 2 中,研究将检验是否在支架上生长辅助肝脏
可以提供导致高精氨酸血症表型纠正所需的最小尿素循环功能。这
该方法可能对其他尿素循环障碍有效。随着拟议研究的成功完成
预计一种基因和细胞替代的新疗法将为患有该病的患者迈出一步
精氨酸酶缺乏症。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Gerald S Lipshutz其他文献
Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia.
首次人体丙酸血症 1/2 mRNA 试验的中期分析。
- DOI:
10.1038/s41586-024-07266-7 - 发表时间:
2024-04-03 - 期刊:
- 影响因子:64.8
- 作者:
Dwight Koeberl;Andreas Schulze;Neal Sondheimer;Gerald S Lipshutz;T. Geberhiwot;Lerong Li;Rajnish Saini;Junxiang Luo;Vanja Sikirica;Ling Jin;Min Liang;Mary Leuchars;Stephanie Grunewald - 通讯作者:
Stephanie Grunewald
Gerald S Lipshutz的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Gerald S Lipshutz', 18)}}的其他基金
Gene Therapy Clinical Candidate Development for Carbamoyl Phosphate Synthetase Deficiency
氨基甲酰磷酸合成酶缺乏症的基因治疗临床候选药物开发
- 批准号:
10339836 - 财政年份:2022
- 资助金额:
$ 34.15万 - 项目类别:
Gene Therapy Clinical Candidate Development for Carbamoyl Phosphate Synthetase Deficiency
氨基甲酰磷酸合成酶缺乏症的基因治疗临床候选药物开发
- 批准号:
10540348 - 财政年份:2022
- 资助金额:
$ 34.15万 - 项目类别:
Understanding the Mechanism and Preventing the Unique Neuropathology of Arginase Deficiency
了解精氨酸酶缺乏的机制并预防独特的神经病理学
- 批准号:
10318637 - 财政年份:2019
- 资助金额:
$ 34.15万 - 项目类别:
Understanding the Mechanism and Preventing the Unique Neuropathology of Arginase Deficiency
了解精氨酸酶缺乏的机制并预防独特的神经病理学
- 批准号:
10540721 - 财政年份:2019
- 资助金额:
$ 34.15万 - 项目类别:
Understanding the Mechanism and Preventing the Unique Neuropathology of Arginase Deficiency
了解精氨酸酶缺乏的机制并预防独特的神经病理学
- 批准号:
10080755 - 财政年份:2019
- 资助金额:
$ 34.15万 - 项目类别:
Understanding the Mechanism and Preventing the Unique Neuropathology of Arginase Deficiency
了解精氨酸酶缺乏的机制并预防独特的神经病理学
- 批准号:
9908195 - 财政年份:2019
- 资助金额:
$ 34.15万 - 项目类别:
Cell and Gene Replacement Strategies for Arginase Deficiency
精氨酸酶缺乏症的细胞和基因替代策略
- 批准号:
10115139 - 财政年份:2017
- 资助金额:
$ 34.15万 - 项目类别:
Development of Molecular Therapy for Carbamoyl Phosphate Synthetase Deficiency
氨基甲酰磷酸合成酶缺乏症分子治疗的进展
- 批准号:
8996735 - 财政年份:2015
- 资助金额:
$ 34.15万 - 项目类别:
Development of Molecular Therapy for Carbamoyl Phosphate Synthetase Deficiency
氨基甲酰磷酸合成酶缺乏症分子治疗的进展
- 批准号:
8872239 - 财政年份:2015
- 资助金额:
$ 34.15万 - 项目类别:
Immunologic Aspects of In Utero or Neonatal AAV-Based Gene Therapy
子宫内或新生儿基于 AAV 的基因治疗的免疫学方面
- 批准号:
8915936 - 财政年份:2014
- 资助金额:
$ 34.15万 - 项目类别:
相似国自然基金
本体驱动的地址数据空间语义建模与地址匹配方法
- 批准号:41901325
- 批准年份:2019
- 资助金额:22.0 万元
- 项目类别:青年科学基金项目
时空序列驱动的神经形态视觉目标识别算法研究
- 批准号:61906126
- 批准年份:2019
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
针对内存攻击对象的内存安全防御技术研究
- 批准号:61802432
- 批准年份:2018
- 资助金额:25.0 万元
- 项目类别:青年科学基金项目
大容量固态硬盘地址映射表优化设计与访存优化研究
- 批准号:61802133
- 批准年份:2018
- 资助金额:23.0 万元
- 项目类别:青年科学基金项目
IP地址驱动的多径路由及流量传输控制研究
- 批准号:61872252
- 批准年份:2018
- 资助金额:64.0 万元
- 项目类别:面上项目
相似海外基金
Executive functions in urban Hispanic/Latino youth: exposure to mixture of arsenic and pesticides during childhood
城市西班牙裔/拉丁裔青年的执行功能:童年时期接触砷和农药的混合物
- 批准号:
10751106 - 财政年份:2024
- 资助金额:
$ 34.15万 - 项目类别:
Identification of Prospective Predictors of Alcohol Initiation During Early Adolescence
青春期早期饮酒的前瞻性预测因素的鉴定
- 批准号:
10823917 - 财政年份:2024
- 资助金额:
$ 34.15万 - 项目类别:
Effects of tACS on alcohol-induced cognitive and neurochemical deficits
tACS 对酒精引起的认知和神经化学缺陷的影响
- 批准号:
10825849 - 财政年份:2024
- 资助金额:
$ 34.15万 - 项目类别:
Early Life Stress Induced Mechanisms of Cardiovascular Disease Risk and Resilience
生命早期压力诱发心血管疾病风险和恢复力的机制
- 批准号:
10555121 - 财政年份:2023
- 资助金额:
$ 34.15万 - 项目类别: